The overall goals of this proposal are to quantitatively characterize the effects on neural activation and cerebral networks of novel compounds that target metabotropic glutamate receptor subype 2 (mGlu2) using functional neuroimaging techniques, and to correlate these findings with behavioral responses. These agents are of high interest as potential treatments for schizophrenia and other mood disorders. Preclinical and phase II clinical data with LY404039 support the hypothesis that metabotropic glutamate receptor subtype 2/3 (mGlu2/3) agonists are a viable, non-dopaminergic strategy for the treatment of schizophrenia. The clinical findings suggest that mGlu2/3 activation is effective in improving both positive and negative symptoms and a study in ketamine-induced working memory deficits in human subjects suggests that cognition can be improved, too. We have recently reported the development of a novel strategy to selectively activate individual mGlu subtypes, particularly mGlu2, using highly selective positive allosteric modulators (PAMs). These compounds do not activate mGlu2 directly, but dramatically potentiate the response of the receptor to Glu. The development of biphenyl indadone-A (BINA), a systemically active mGlu2 PAM that crosses the blood brain barrier, opens an unprecedented opportunity to investigate whether the antipsychotic-like effects of mGlu2/3 agonists can be recapitulated by targeting mGlu2 with a PAM. Our preliminary studies suggest that BINA has robust efficacy in several animal models used to predict antipsychotic efficacy. In the proposed studies, we will utilize BINA and the mGlu2/3 agonist LY404039 in a series of neuroimaging studies to test the hypothesis that selective potentiation of mGlu2 will have activity in animal models that predict antipsychotic efficacy. We hypothesize that these agents will modulate glutamatergic transmission in corticostriatal and corticothalamic circuits and that direct mGlu2/3 activation wil differentially modulate mesolimbic dopamine transmission compared to mGlu2 potentiation. Using resting state functional MRI as an output in NMDA receptor hypofunction models, we predict mGlu2-mediated normalization of neural network fluctuations. We will correlate the imaging findings with treatment effects on cognition tasks. Normalization of resting state brain fluctuations may be an important biomarker of the therapeutic efficacy of antipsychotic agents.